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Donato Rigante http://orcid.org/0000-0001-7032-7779
Raffaele Manna, Prof.


Familial Mediterranean fever, autoinflammation, periodic fever, colchicine, interleukin-1, innovative biotechnologies, anakinra, canakinumab, personalized medicine


Recurrent self-limited attacks of fever and short-lived inflammation in the serosal membranes, joints and skin are the leading features of familial Mediterranean fever (FMF), the most common autoinflammatory disorder in the world, transmitted as autosomal recessive trait caused by MEFV gene mutations. Their consequence is an abnormal function of pyrin, a natural repressor of inflammation, apoptosis and release of cytokines. FMF-related mutant pyrins are hypophosphorylated following RhoA GTPases’ impaired activity and show a propensity to relapsing uncontrolled systemic inflammation with inappropriate response to inflammatory stimuli and leukocyte spread to serosal membranes, joints or skin. Typical FMF phenotype 1 consists of brief episodes of inflammation and serositis, synovitis, and/or erysipelas-like eruption, whereas phenotype 2 is defined by reactive amyloid-associated (AA) amyloidosis, which is the most ominous complication of FMF, in otherwise asymptomatic individuals. Furthermore, FMF phenotype 3 is referred to the presence of two MEFV mutations with neither clinical signs of FMF, nor AA amyloidosis. The influence of epigenetic and/or environmental factors can contribute to the variable penetrance and phenotypic heterogeneity of FMF. Colchicine, a tricyclic alkaloid with anti-microtubule and anti-inflammatory properties, is the bedrock of FMF management: daily administration of colchicine prevents the recurrence of FMF attacks and the development of secondary AA amyloidosis. Many recent studies have also shown that anti-interleukin-1 treatment is actually the best therapeutic option for FMF patients nonresponsive or intolerant to colchicine. This review aims to catch readers’ attention on the clinical diversity of phenotypes, differential diagnosis, and management of patients with FMF.


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1) Stojanov S, Kastner DL. Familial autoinflammatory diseases: genetics, pathogenesis and treatment. Curr Opin Rheumatol 2005;17:586-99. PMid: 16093838

2) Ozen S, Demir S. Monogenic periodic fever syndromes: treatment options for the pediatric patient. Paediatr Drugs 2017;19:303-1. doi: 10.1007/s40272-017-0232-6 PMid: 28497352

3) Rigante D. The broad-ranging panorama of systemic autoinflammatory disorders with specific focus on acute painful symptoms and hematologic manifestations in children. Mediterr J Hematol Infect Dis 2018;10(1):e2018067 doi: 10.4084/MJHID.2018.067 PMid: 30416699

4) Rigante D. A developing portrait of hereditary periodic fevers in childhood. Expert Opin Orphan Drugs 2018;6:47-55. doi: 10.1080/21678707.2018.1406797

5) Siegal S. Benign paroxysmal peritonitis. Gastroenterology 1949;12:234-47. PMid : 18124924

6) Reimann HA, Moadie J, Semerdjian S, Sahyoun PF. Periodic peritonitis; heredity and pathology: report of seventy-two cases. J Am Med Assoc 1954;154:1254-9. PMid: 13151833

7) Heller H, Sohar E, Sherf L. Familial Mediterranean fever. AMA Arch Int Med 1958;102:50-71. PMid: 13558745

8) Babior BM, Matzner Y. The familial Mediterranean fever gene - cloned at last. N Engl J Med 1997;337:1548-9. doi: 10.1056/NEJM199711203372112 PMid: 9366590

9) Booth DR, Gillmore JD, Booth SE, et al. Pyrin/marenostrin mutations in familial Mediterranean fever. QJM 1998;91:603-6. PMid: 10024914

10) Rigante D. The fresco of autoinflammatory diseases from the pediatric perspective. Autoimmun Rev 2012;11:348-56. doi: 10.1016/j.autrev.2011.10.008 PMid: 22024500

11) Rigante D. The protean visage of systemic autoinflammatory syndromes: a challenge for inter-professional collaboration. Eur Rev Med Pharmacol Sci 2010;14:1-18. PMid: 20184084

12) Fujikura K. Global epidemiology of familial Mediterranean fever mutations using population exome sequences. Mol Genet Genomic Med 2015;3:272-82. doi: 10.1002/mgg3.140 PMid: PMC4521964

13) Touitou I. The spectrum of familial Mediterranean fever mutations. Eur J Hum Genet 2001;9:473-83. PMid: 11464238

14) Gershoni-Baruch R, Shinawi M, Leah K, et al. Familial Mediterranean fever: prevalence, penetrance and genetic drift. Eur J Hum Genet 2001;9:634-7. doi: 10.1038/sj.ejhg.5200672 PMid: 11528510

15) Lidar M, Livneh A. Familial Mediterranean fever: clinical, molecular and management advancements. Neth J Med 2007;65:318-24. PMid: 17954950

16) Manna R, Cerquaglia C, Curigliano V, et al. Clinical features of familial Mediterranean fever: an Italian overview. Eur Rev Med Pharmacol Sci 2009;13 Suppl 1:51-3. PMid: 19530512

17) Rigante D, Frediani B, Galeazzi M, et al. From the Mediterranean to the sea of Japan: the transcontinental odyssey of autoinflammatory diseases. Biomed Res Int 2013;2013:485103. doi: 10.1155/2013/485103 PMid: 23971037

18) Tunca M, Akar S, Onen F, et al. Familial Mediterranean fever in Turkey: results of a nationwide multicenter study. Medicine 2005 84:1-11. PMid: 15643295

19) Lucherini OM, Rigante D, Sota J, et al. Updated overview of molecular pathways involved in the most common monogenic autoinflammatory diseases. Clin Exp Rheumatol 2018;36 Suppl 110(1):3-9. PMid: 29742053

20) Alghamdi M. Familial Mediterranean fever, review of the literature. Clin Rheumatol 2017;36:1707-13. doi: 10.1007/s10067-017-3715-5 PMid: 28624931

21) Bagci S, Toy B, Tuzun A, et al. Continuity of cytokine activation in patients with familial Mediterranean fever. Clin Rheumatol 2004;23:333-7. doi: 10.1007/s10067-004-0925-4 PMid: 15293095

22) Kelesoglu FM, Aygun E, Okumus NK, et al. Evaluation of subclinical inflammation in familial Mediterranean fever patients: relations with mutation types and attack status: a retrospective study. Clin Rheumatol 2016;35:2757-63. doi: 10.1007/s10067-016-3275-0 PMid: 27106545

23) Van Gorp H, Saavedra PH, de Vasconcelos NM, et al. Familial Mediterranean fever mutations lift the obligatory requirement for microtubules in pyrin inflammasome activation. Proc Natl Acad Sci USA 2016;113:14384-9. doi: 10.1073/pnas.1613156113 PMid: 27911804

24) Park YH, Wood G, Kastner DL, et al. Pyrin inflammasome activation and RhoA signaling in the autoinflammatory diseases FMF and HIDS. Nat Immunol 2016;17:914-21. doi: 10.1038/ni.3457 PMid: 27270401

25) Demirtürk L, Ozel AM, Cekem K, et al. Co-existence of Helicobacter pylori infection in patients with familial Mediterranean fever (FMF) and the effect of Helicobacter pylori on the frequency and severity of FMF attacks. Dig Liver Dis 2005;37:153-8. doi: 10.1016/j.dld.2004.09.027 PMid: 15888278

26) Verrecchia E, Sicignano LL, La Regina M, et al. Small intestinal bacterial overgrowth affects the responsiveness to colchicine in familial Mediterranean fever. Mediators Inflamm 2017;2017:7461426. doi: 10.1155/2017/7461426 PMid: 29379228

27) Rigante D, La Torraca I, Avallone L, et al. The pharmacological basis of treatment with colchicine in children with familial Mediterranean fever. Eur Rev Med Pharmacol Sci 2006;10:173-8. PMid: 16910346

28) Rigante D. A systematic approach to autoinflammatory syndromes: a spelling booklet for the beginner. Expert Rev Clin Immunol 2017;13:571-97. doi: 10.1080/1744666X.2017.1280396 PMid: 28064547

29) Dodé C, Pecheux C, Cazeneuve C, et al. Mutations in the MEFV gene in a large series of patients with a clinical diagnosis of familial Mediterranean fever. Am J Med Genet 2000;92:241-6. PMid: 10842288

30) Shinar Y, Livneh A, Langevitz P, et al. Genotype-phenotype assessment of common genotypes among patients with familial Mediterranean fever. J Rheumatol 2000; 27:1703-7. PMid: 10914855

31) Pasa S, Altintas A, Devecioglu B, et al. Familial Mediterranean fever gene mutations in the Southeastern region of Turkey and their phenotypical features. Amyloid 2008;15:49-53. doi: 10.1080/13506120701815456 PMid: 18266121

32) Ben-Chetrit E, Touitou I. Familial Mediterranean fever in the world. Arthritis Rheum 2009;61:1447-53. doi: 10.1002/art.24458 PMid: 19790133

33) Booth DR, Lachmann HJ, Gillmore JD, et al. Prevalence and significance of the familial Mediterranean fever gene mutation encoding pyrin Q148. QJM 2001;94:527-31. PMid: 11588211

34) Comak E, Akman S, Koyun M, et al. Clinical evaluation of R202Q alteration of MEFV genes in Turkish children. Clin Rheumatol 2014;33:1765-71. doi: 10.1007/s10067-014-2602-6 PMid: 24718488

35) Gershoni-Baruch R, Brik R, Zacks N, et al. The contribution of genotypes at the MEFV and SAA1 loci to amyloidosis and disease severity in patients with familial Mediterranean fever. Arthritis Rheum 2003;48:1149-55. doi: 10.1002/art.10944 PMid: 12687559

36) Caso F, Costa L, Rigante D, et al. Caveats and truths in genetic, clinical, autoimmune and autoinflammatory issues in Blau syndrome and early onset sarcoidosis. Autoimmun Rev 2014;13:1220-9. doi: 10.1016/j.autrev.2014.08.010 PMid: 25182201

37) Berkun Y, Karban A, Padeh S, et al. NOD2/CARD15 gene mutations in patients with familial Mediterranean fever. Semin Arthritis Rheum 2012;42:84-8. doi: 10.1016/j.semarthrit.2011.12.002 PMid: 22244368

38) Rigante D. New mosaic tiles in childhood hereditary autoinflammatory disorders. Immunol Lett 2018;193:67-76. doi: 10.1016/j.imlet.2017.11.013 PMid: 29198619

39) Rigante D, La Torraca I, Ansuini V, et al. The multi-face expression of familial Mediterranean fever in the child. Eur Rev Med Pharmacol Sci 200;10:163-71. PMid: 16910345

40) Soriano A, Manna R. Familial Mediterranean fever: new phenotypes. Autoimmun Rev 2012;12:31-7. doi: 10.1016/j.autrev.2012.07.019 PMid: 22878273

41) El-Shanti H, Majeed HA, El-Khateeb M. Familial mediterranean fever in Arabs. Lancet. 2006 Mar 25;367(9515):1016-24. doi: 10.1016/S0140-6736(06)68430-4 PMid: 16564365

42) Adrovic A, Sahin S, Barut K, et al. Familial Mediterranean fever and periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome: shared features and main differences. Rheumatol Int 2019;39:29-36. doi: 10.1007/s00296-018-4105-2 PMid: 30019226

43) Gentileschi S, Vitale A, Frediani B, et al. Challenges and new horizons in the periodic fever, aphthous stomatitis, pharingitis and adenitis (PFAPA) syndrome. Expert Opin Orphan Drugs 2017;5:165-71. doi: 10.1080/21678707.2017.1279049

44) Gaggiano C, Rigante D, Sota J, et al. Treatment options for periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome in children and adults: a narrative review. Clin Rheumatol 2018 Nov 28. doi: 10.1007/s10067-018-4361-2 PMid: 30488366

45) Cantarini L, Vitale A, Bartolomei B, et al. Diagnosis of PFAPA syndrome applied to a cohort of 17 adults with unexplained recurrent fevers. Clin Exp Rheumatol 2012;30:269-71. PMid: 22325152

46) Rigante D, Vitale A, Natale MF, et al. A comprehensive comparison between pediatric and adult patients with periodic fever, aphthous stomatitis, pharyngitis, and cervical adenopathy (PFAPA) syndrome. Clin Rheumatol 2017;36:463-8. doi: 10.1007/s10067-016-3317-7 PMid: 27251674

47) Cakir M, Ozgenc F, Baran M, et al. A rare cause of refractory ascites in a child: familial Mediterranean fever. Rheumatol Int 2010;30:531-4. doi: 10.1007/s00296-009-0957-9 PMid: 19466424

48) Reissman P, Durst Al, Rivkind A, et al. Elective laparoscopic appendectomy in patients with familial Mediterranean fever. World J Surg 1994;18:139-42. PMid: 8197770

49) Kees S, Langevitz P, Zemer D, et al. Attacks of pericarditis as a manifestation of familial Mediterranean fever. QJM 1997;90:643-7. PMid: 9415347

50) Rigante D, Cantarini L, Imazio M, et al. Autoinflammatory diseases and cardiovascular manifestations. Ann Med 2011;43:341-6. doi: 10.3109/07853890.2010.547212 PMid: 21284530

51) Eshel G, Vinograd I, Barr J, et al. Acute scrotal pain complicating familial Mediterranean fever in children. Br J Surg 1994; 81: 894-6. PMid: 8044614

52) Jarjour RA, Dodaki R. Arthritis patterns in familial Mediterranean fever patients and association with M694V mutation. Mol Biol Rep 2011;38:2033-6. doi: 10.1007/s11033-010-0326-5 PMid: 20845072

53) Rigante D, Cantarini L. Monogenic autoinflammatory syndromes at a dermatological level. Arch Dermatol Res 2011;303:375-80. doi: 10.1007/s00403-011-1134-z PMid: 21340744

54) Kotevoglu N, Sahin F, Ozkiris SO, et al. Protracted febrile myalgia of familial Mediterranean fever. Clin Exp Rheumatol 2004;22:S69-S70. PMid: 15515790

55) Tufan G, Demir S. Uncommon clinical pattern of FMF: protracted febrile myalgia syndrome. Rheumatol Int 2010;30:1089-90. doi: 10.1007/s00296-009-1024-2 PMid: 19590876

56) Rigante D, Lopalco G, Tarantino G, et al. Non-canonical manifestations of familial Mediterranean fever: a changing paradigm. Clin Rheumatol 2015;34:1503-11. doi: 10.1007/s10067-015-2916-z PMid: 25761640

57) Feld O, Yahalom G, Livneh A. Neurologic and other systemic manifestations in FMF: published and own experience. Best Pract Res Clin Rheumatol 2012;26:119-33. doi: 10.1016/j.berh.2012.01.004 PMid: 22424198

58) Medlej-Hashim M, Delague V, Chouery E, et al. Amyloidosis in familial Mediterranean fever patients: correlation with MEFV genotype and SAA1 and MICA polymorphisms effects. BMC Med Genet 2004;5:4. PMid: 15018633

59) Touitou I, Sarkisian T, Medlej-Hashim M, et al. Country as the primary risk factor for renal amyloidosis in familial Mediterranean fever. Arthritis Rheum 2007;56:1706-12. doi: 10.1002/art.22507 PMid: 17469185

60) Rigante D, Frediani B, Cantarini L. A comprehensive overview of the hereditary periodic fever syndromes. Clin Rev Allergy Immunol 2018;54:446-53. doi: 10.1007/s12016-016-8537-8 PMid: 27068928

61) Lange-Sperandio B, Möhring K, Gutzler F, et al. Variable expression of vasculitis in siblings with familial Mediterranean fever. Pediatr Nephrol 2004;19:539-43. doi: 10.1007/s00467-004-1440-1 PMid: 15015067

62) Soriano A, Pras E. Familial Mediterranean fever: genetic update. Isr Med Assoc J 2014;16:274-6. PMid: 24979829

63) Stabile A, Bertoni B, Ansuini V, et al. The clinical spectrum and treatment options of macrophage activation syndrome in the pediatric age. Eur Rev Med Pharmacol Sci 2006;10:53-9. PMid: 16705949

64) Rigante D, Emmi G, Fastiggi M, et al. Macrophage activation syndrome in the course of monogenic autoinflammatory disorders. Clin Rheumatol 2015;34:1333-9. doi: 10.1007/s10067-015-2923-0 PMid: 25846831

65) Brenner R, Ben-Zvi I, Shinar Y, et al. Familial Mediterranean fever and incidence of cancer: an analysis of 8,534 Israeli patients with 258,803 person-years. Arthritis Rheumatol 2018;70:127-33. doi: 10.1002/art.40344 PMid: 28992365

66) Sohar E, Gafni J, Pras M, et al. Familial Mediterranean fever. A survey of 470 cases and review of the literature. Am J Med 1967;43:227-53. PMid: 5340644

67) Livneh A, Langevitz P, Zemer D, et al. Criteria for the diagnosis of familial Mediterranean fever. Arthritis Rheum 1997;40:1879-85. doi: 10.1002/1529-0131(199710)40 PMid: 9336425

68) Yalçinkaya F, Ozen S, Ozçakar ZB, et al. A new set of criteria for the diagnosis of familial Mediterranean fever in childhood. Rheumatology (Oxford) 2009;48:395-8. doi: 10.1093/rheumatology/ken509 PMid: 19193696

69) Demirkaya E, Saglam C, Turker T, et al. Performance of different diagnostic criteria for Familial Mediterranean fever in children with periodic fevers: results from a multicenter international registry. J Rheumatol 2016;43:154-60. doi: 10.3899/jrheum.141249 PMid: 26568587

70) Federici S, Sormani MP, Ozen S, et al. Evidence-based provisional clinical classification criteria for autoinflammatory periodic fevers. Ann Rheum Dis 2015;74:799-805. doi: 10.1136/annrheumdis-2014-206580 PMid: 25637003

71) Yepiskoposyan L, Harutyunyan A. Population genetics of familial Mediterranean fever: a review. Eur J Hum Genet 2007; 15: 911-6. doi: 10.1038/sj.ejhg.5201869 PMid: 17568393

72) Caso F, Cantarini L, Lucherini OM, et al. Working the endless puzzle of hereditary autoinflammatory disorders. Mod Rheumatol 2014;24:381-9. doi: 10.3109/14397595.2013.843755 PMid: 24251993

73) Hentgen V, Grateau G, Stankovic-Stojanovic K, et al. Familial Mediterranean fever in heterozygotes: are we able to accurately diagnose the disease in very young children? Arthritis Rheum 2013;65:1654-62. doi: 10.1002/art.37935 PMid: 23508419

74) Zemer D, Pras M, Sohar E, et al. Colchicine in the prevention and treatment of the amyloidosis of familial Mediterranean fever. N Engl J Med 1986;314:1001-5. doi: 10.1056/NEJM198604173141601 PMid: 3515182

75) Rigante D, Vitale A, Lucherini OM, et al. The hereditary autoinflammatory disorders uncovered. Autoimmun Rev 2014;13:892-900. doi: 10.1016/j.autrev.2014.08.001 PMid: 25149390

76) Knieper AM, Klotsche J, Lainka E, et al. Familial Mediterranean fever in children and adolescents: factors for colchicine dosage and predicting parameters for dose increase. Rheumatology (Oxford) 2017;56:1597-606. doi: 10.1093/rheumatology/kex222 PMid: 2885939

77) Yanmaz MN, Özcan AJ, Savan K. The impact of familial Mediterranean fever on reproductive system. Clin Rheumatol 2014;33:1385-8. doi: 10.1007/s10067-014-2709-9 PMid: 24924605

78) Ozturk MA, Kanbay M, Kasapoglu B, et al. Therapeutic approach to familial Mediterranean fever: a review update. Clin Exp Rheumatol. 2011;29(4 Suppl 67):S77-86. PMid: 21968242

79) Eroglu FK, Be?ba? N, Topaloglu R, et al. Treatment of colchicine-resistant Familial Mediterranean fever in children and adolescents. Rheumatol Int 2015;35:1733-7. doi: 10.1007/s00296-015-3293-2 PMid: 26001859

80) Corsia A, Georgin-Lavialle S, Hentgen V, et al. A survey of resistance to colchicine treatment for French patients with familial Mediterranean fever. Orphanet J Rare Dis 2017;12:54. doi: 10.1186/s13023-017-0609-1 PMid: 28302131

81) Cerquaglia C, Diaco M, Nucera G, et al. Pharmacological and clinical basis of treatment of familial Mediterranean fever (FMF) with colchicine or analogues: an update. Curr Drug Targets Inflamm Allergy 2005;4:117-24. PMid: 15720245

82) Ben-Zvi I, Krichely-Vachdi T, Feld O, et al. Colchicine-free remission in familial Mediterranean fever: featuring a unique subset of the disease-a case control study. Orphanet J Rare Dis 2014;9:3. doi: 10.1186/1750-1172-9-3 PMid: 24401676

83) Tamir N, Langevitz P, Zemer D, et al. Late-onset familial Mediterranean fever (FMF): a subset with distinct clinical, demographic, and molecular genetic characteristics. Am J Med Genet 1999;87:30-5. PMid: 10528243

84) Rigante D, Manna R. A position for tumor necrosis factor inhibitors in the management of colchicine-resistant familial Mediterranean fever? Immunol Lett 2016;180:77-8. doi: 10.1016/j.imlet.2016.10.007 PMid: 27984066

85) Lopalco G, Cantarini L, Vitale A, et al. Interleukin-1 as a common denominator from autoinflammatory to autoimmune disorders: premises, perils, and perspectives. Mediators Inflamm 2015;2015:194864. doi: 10.1155/2015/194864 PMid: 25784780

86) Cantarini L, Lopalco G, Cattalini M, et al. Interleukin-1: Ariadne's thread in autoinflammatory and autoimmune disorders. Isr Med Assoc J 2015;17:93-7. PMid: 26223084

87) Cantarini L, Lucherini OM, Frediani B, et al. Bridging the gap between the clinician and the patient with cryopyrin-associated periodic syndromes. Int J Immunopathol Pharmacol 2011;24:827-36. doi: 10.1177/039463201102400402 PMid: 22230390

88) Varan Ö, Kucuk H, Babaoglu H, et al. Efficacy and safety of interleukin-1 inhibitors in familial Mediterranean fever patients complicated with amyloidosis. Mod Rheumatol 2018 Apr 27:1-4. doi: 10.1080/14397595.2018.1457469 PMid: 29578360

89) De Benedetti F, Gattorno M, Anton J, et al. Canakinumab for the treatment of autoinflammatory recurrent fever syndromes. N Engl J Med 2018;378:1908-19. doi: 10.1056/NEJMoa1706314 PMid: 29768139

90) Vitale A, Insalaco A, Sfriso P, et al. A snapshot on the on-label and off-label use of the interleukin-1 inhibitors in Italy among rheumatologists and pediatric rheumatologists: a nationwide multi-center retrospective observational study. Front Pharmacol 2016;7:380. doi: 10.3389/fphar.2016.00380 PMid: 27822185

91) Mor A, Shinar Y, Zaks N, et al. Evaluation of disease severity in familial Mediterranean fever. Semin Arthritis Rheum 2005;35:57-64. doi: 10.1016/j.semarthrit.2005.02.002 PMid: 16084225

92) Cantarini L, Lucherini OM, Iacoponi F, et al. Development and preliminary validation of a diagnostic score for identifying patients affected with adult-onset autoinflammatory disorders. Int J Immunopathol Pharmacol 2010;23:1133-4. doi: 10.1177/039463201002300417 PMid: 21244762

93) Cantarini L, Iacoponi F, Lucherini OM, et al. Validation of a diagnostic score for the diagnosis of autoinflammatory diseases in adults. Int J Immunopathol Pharmacol 2011;24:695-702. doi: 10.1177/039463201102400315 PMid: 21978701

94) Piram M, Koné Paut I, Lachmann H, et al. Validation of the auto-inflammatory diseases activity index (AIDAI) for hereditary recurrent fever syndromes. Ann Rheum Dis 2014;73:2168-73. doi: 10.1136/annrheumdis-2013-203666 PMid: 24026675

95) Ter Haar NM, Annink KV, Al-Mayouf SM, et al. Development of the autoinflammatory disease damage index (ADDI). Ann Rheum Dis 2017;76:821-30. doi: 10.1136/annrheumdis-2016-210092 PMid: 27811147

96) Ter Haar NM, van Delft ALJ, Annink KV, et al. In silico validation of the Autoinflammatory Disease Damage Index. Ann Rheum Dis 2018;77:1599-1605. doi: 10.1136/annrheumdis-2018-213725 PMid: 30077992

97) Rigante D. Autoinflammatory syndromes behind the scenes of recurrent fevers in children. Med Sci Monit 2009;15:RA179-87. PMid: 19644432

98) Dusser P, Hentgen V, Neven B, et al. Is colchicine an effective treatment in periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis (PFAPA) syndrome? Joint Bone Spine 2016;83:406-11. doi: 10.1016/j.jbspin.2015.08.017 PMid: 27068612

99) Caso F, Costa L, Rigante D, et al. Biological treatments in Behçet’s disease: beyond anti-TNF-therapy. Mediators Inflamm 2014;2014:107421. doi: 10.1155/2014/107421 PMid: 25061259

100) Watad A, Tiosano S, Yahav D, et al. Behçet's disease? and familial Mediterranean fever: Two sides of the same coin or just an association? A cross-sectional study?. Eur J Intern Med 2017;39:75-8. doi: 10.1016/j.ejim.2016.10.011 PMid: 27776949

101) Ter Haar NM, Jeyaratnam J, Lachmann HJ, et al. The phenotype and genotype of mevalonate kinase deficiency: a series of 114 cases from the Eurofever Registry. Arthritis Rheumatol 2016;68:2795-805. doi: 10.1002/art.39763 PMid: 27213830

102) Esposito S, Ascolese B, Senatore L, et al. Current advances in the understanding and treatment of mevalonate kinase deficiency. Int J Immunopathol Pharmacol 2014;27:491-8. doi: 10.1177/039463201402700404 PMid: 25572728

103) Rigante D, Lopalco G, Vitale A, et al. Key facts and hot spots on tumor necrosis factor receptor-associated periodic syndrome. Clin Rheumatol 2014;33:1197-207. doi: 10.1007/s10067-014-2722-z PMid: 24935411

104) Naik H, Stoecker M, Sanderson SC, et al. Experiences and concerns of patients with recurrent attacks of acute hepatic porphyria: A qualitative study. Mol Genet Metab 2016;119:278-83. doi: 10.1016/j.ymgme.2016.08.006 PMid: 27595545

105) Cantarini L, Rigante D, Brizi MG, et al. Clinical and biochemical landmarks in systemic autoinflammatory diseases. Ann Med 2012;44:664-73. doi: 10.3109/07853890.2011.598546 PMid: 21972825

106) Cantarini L, Vitale A, Lucherini OM, et al. Childhood versus adulthood-onset autoinflammatory disorders: myths and truths intertwined. Reumatismo 2013;65:55-62. doi: 10.4081/reumatismo.2013.55 PMid: 23877409

107) Rigante D, Vitale A, Natale MF, et al. Lights and shadows in autoinflammatory syndromes from the childhood and adulthood perspective. Clin Rheumatol 2016;35:565-72. doi: 10.1007/s10067-015-3132-6 PMid: 26631101

108) Vitale A, Rigante D, Lucherini OM, et al. The diagnostic evaluation of patients with a suspected hereditary periodic fever syndrome: experience from a referral center in Italy. Intern Emerg Med 2017;12:605-11. doi: 10.1007/s11739-017-1622-z PMid: 28194697